Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity

Oliveira, Juliana R.; Bertolin, Thiago Carlos; Andrade, de; Oliveira, Larissa Costa; Kondo, Márcia Y.; Santos, Jorge A.N.; Blaber, Michael; Juliano, Luiz; Severino, Beatrice; Caliendo, Giuseppe; Santagada, Vincenzo; Juliano, María A.

doi:10.1016/j.bbapap.2014.10.018

Cited by 18 publications

(21 citation statements)

References 74 publications

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“…2). Because we did not observe binding of DS or CS by vaspin in MST experiments, this slight increase is probably due to moderate activation of KLK7, as reported previously (16 The fit yielded a K D of 99.1 nM. C, normalized fluorescence (F norm) for LMWH oligosaccharides fondaparinux and dp8 as well as dermatan sulfate (DS) and chondroitin sulfate (CS) titrated to vaspin (100 nM).…”

Section: Activation Of Vaspin By Gags-heparin Accelerates Klk7mentioning

confidence: 73%

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Ulbricht

Oertwig

Arnsburg

et al. 2017

Journal of Biological Chemistry

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Vaspin (serpin A12) was identified in adipose tissue of the OLETF rat type-2 diabetes model and functions as an antidiabetic and anti-atherogenic adipokine in obesity-related disorders, such as insulin resistance and inflammation (1, 2). Insulin-resistant mouse models exhibit improved glucose tolerance after intraperitoneal vaspin application (3, 4), and transgenic mice overexpressing vaspin are protected from diet-induced obesity and comorbidities, such as glucose intolerance, insulin resistance, and adipose tissue inflammation (5). We found that intraperitoneal and central administration of vaspin leads to reduced food intake and blood glucose in mice (6). A recent study demonstrated that central vaspin regulates hepatic glucose production and insulin signaling via brain-liver communication through the dorsal vagal complex (7). In endothelial and vascular smooth muscle cells, multiple studies demonstrated anti-apoptotic (8), anti-inflammatory (9), and anti-migratory (10) effects of vaspin, suggesting a protective role in the pathogenesis of atherosclerosis. In skin, vaspin expression by keratinocytes suppresses the expression and release of inflammatory cytokines by immune cells (11) and possibly regulates the activation of proinflammatory cytokines, such as chemerin, via KLK7 (12). Whereas vaspin-mediated improvement of glucose tolerance and reduction of food intake were found to be dependent on protease inhibition (4, 13), anti-inflammatory effects in the liver have been linked to interaction with a membrane-associated endoplasmic reticulum chaperone protein (5).The only protease target of vaspin known so far is human KLK7 (4), a member of a family of 15 serine peptidases with chymotrypsin-like specificity (14). A non-inhibitory vaspin mutant failed to improve glucose tolerance in obese mice, proving that protease inhibition is a prerequisite for vaspin effects on glucose disposal (4). Human insulin is a substrate of KLK7, and vaspin and KLK7 are co-expressed in murine pancreatic islets. We hypothesized that KLK7 inhibition by vaspin may prolong insulin action and increase glucose uptake in insulinresponsive tissues, such as adipose tissue, liver, muscle, and also brain.We have recently reported that the inhibition of KLK7 by vaspin is critically dependent on an arginine residue in proximity to the reactive center loop (RCL), 2 because the native P1Ј glutamate residue is essentially repressing inhibition of KLK7 (15). Inhibition of KLK7 by vaspin is furthermore accelerated by heparin (15). Yet, the nature of the interaction between glycosaminoglycans and vaspin has not been explored in much detail.

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Section: Activation Of Vaspin By Gags-heparin Accelerates Klk7mentioning

confidence: 73%

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Ulbricht

Oertwig

Arnsburg

et al. 2017

Journal of Biological Chemistry

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“…This activation was described for insect-cell-derived, non-natively-glycosylated KLK13 and, therefore, these results must be treated with caution. Recently, KLK7 showed increased activity when it was incubated with GAGs [53]. Heparan sulfate also facilitates interactions between kallikreins and their substrates.…”

Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 99%

“…The anion-dependent activation of KLK6 followed the Hofmeister series, citrate > sulfate > acetate > chloride, but only at pH 7.5. In contrast to the observed activating effects of the kosmotropic salts sodium citrate and sodium sulfate on KLK-3, -6 and -13, these salts reduced KLK7 and KLK1 activity at concentrations up to approximately 250 mM [53]. The activity of KLK7 returned to its initial level at concentrations close to 1.2 M for both salts, but KLK1 recovered only half of the initial activity at this high salt concentration.…”

Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 99%

Kallikreins – The melting pot of activity and function

et al. 2016

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The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Because of the broad spectrum of processes that are modulated by kallikreins, these proteases are the subject of extensive investigations. This review brings together basic information about the biochemical properties affecting enzymatic activity, with highlights on post-translational modifications, especially glycosylation. Additionally, we present the current state of knowledge regarding the physiological functions of KLKs in major human organs and outline recent discoveries pertinent to the involvement of kallikreins in cell signaling and in viral infections. Despite the current depth of knowledge of these enzymes, many questions regarding the roles of kallikreins in health and disease remain unanswered.

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“…Thus, KLK7 is a potential therapeutic target for human colon cancer (58). KLK7 specifically participates in pathophysiological events associated with skin disorder, gastrointestinal tract injury and central nervous system diseases (59). In this study, KLK7 was found to be highly expressed in gastric tissue and it was found that i may cause gastric injury, as indicated by gastrointestinal endoscopy.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia

Gesang

Zhang

et al. 2016

International Journal of Molecular Medicine

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High altitude-associated polycythemia (HAPC) is a very common disease. However, it the disease is still unmanageable and the related molecular mechanisms remain largely unclear. In the present study, we aimed to explore the molecular mechanisms responsible for the development of HAPC using transcriptome analysis. Transcriptome analysis was conducted in 3 pairs of gastric mucosa tissues from patients with HAPC and healthy residents at a similar altitude. Endoscopy and histopathological analyses were used to examine the injury to gastric tissues. Molecular remodeling was performed for the interaction between different KLK members and cholesterol. HAPC was found to lead to morphological changes and pathological damage to the gastric mucosa of patients. A total of 10,304 differentially expressed genes (DEGs) were identified. Among these genes, 4,941 DEGs were upregulated, while 5,363 DEGs were downregulated in the patients with HAPC (fold change ≥2, P<0.01 and FDR <0.01). In particular, the kallikrein gene cluster (KLK1/3/7/8/12) was upregulated >17-fold. All the members had high-score binding cholesterol, particularly for the polymers of KLK7. The kallikrein gene cluster (KLK1/3/7/8/12) is on chromosome 19q13.3–13.4. The elevated levels of KLK1, KLK3, KLK7, KLK8 and KLK12 may be closely associated with the hypertension, inflammation, obesity and other gastric injuries associated with polycythemia. The interaction of KLKs and cholesterol maybe play an important role in the development of hypertension. The findings of the present study revealed that HAPC induces gastric injury by upregulating the kallikrein gene cluster (KLK1/3/7/8/12), which can bind cholesterol and result in kallikrein hypertension. These findings provide some basic information for understanding the molecular mechanisms responsible for HAPC and HAPC-related diseases.

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Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity

Cited by 18 publications

References 74 publications

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Kallikreins – The melting pot of activity and function

Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia

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